Poly[ethylene glycol] (PEG) polymers are widely used by pharma to enhance the physical, chemical, and/or biological nature of promising drug candidates. The process of adding PEG polymers to drug cargo is termed PEGylation and has resulted in several $Billion/year drugs. PEGylation protects the cargo when in the body and prolongs therapeutic action. For patients, these attributes translate to improved drug delivery via fewer injections with fewer side effects. However, the toxicity of PEG's degradation products, the upper size limit for controlled polymerization, and the rising occurrence of immunogenicity (occurrence of PEG-antibodies up from ~0.2% in 1984 to ~22-25% in 2001 which may in part be spawned by PEG-containing consumer products) are still problematic. Therefore, pharma is interested in PEG alternatives for next generation medicines;we have letters of support from industry for our new delivery system. INNOVATION: Caisson Biotech LLC, an Oklahoma biotech company, and The University of Oklahoma are collaborating to develop and commercialize a platform technology, HEPylation(tm), to add a heparosan polymer to therapeutic cargo as a viable alternative to PEGylation. Heparosan, a new type of therapeutic modifying agent, is a natural "self" polysaccharide related to heparin. Caisson's technology also allows for synthesis of sugar polymers with a very narrow size distribution and defined chemical activation that facilitates selective coupling to therapeutics. HEPylation has superior attributes over PEGylation including natural degradation pathways, ease of longer polymer size synthesis, and lower potential for immunogenicity. APPROACH: In this SBIR Phase I project, the two P.I.s will focus on creating and testing HEPylated versions of a current drug, a long acting version of granulocyte colony stimulating factor (G-CSF) used in the treatment of neutropenia (abnormally low white blood cell counts). PEGylated G-CSF, Neulasta ($4.6 Billion in sales in 2009), is commonly employed to prevent infection after anti-cancer chemotherapy or other maladies as well as promises hope for Alzheimer's. PEGylated G-CSF is an improved drug compared to G-CSF alone, but PEG antibodies will increasingly negate its benefit in the future. Therefore, the P.I.s will construct a series of HEPylated G-CSF conjugates and assess their suitability as replacements for the existing drug, Neulasta. The proof of concept syntheses, cell-based and animal feasibility experiments, and the initial toxicology test in Phase I will result in lead drug selection. Later Phase II studies will expand the animal efficacy and toxicology data set. Overall, the SBIR-generated pre-clinical information will be key for: (a) initiating a pre- Investigational New Drug application meeting with the FDA and (b) accelerating commercialization by reducing the technical risk such that a pharma partner will collaborate with Caisson Biotech and support human clinical trials in Phase III. Furthermore, validating the HEPylation platform with this prototype drug promises to expand the drug delivery technology for use with other needed medicines. PUBLIC HEALTH RELEVANCE: The drug delivery system developed in this project will provide an improved alternative to artificial poly[ethylene glycol] (PEG) systems currently used by pharma that are potentially being undermined by a plethora of PEG- containing consumer products including toothpaste, cosmetics, processed foods, and laxatives such that ~22-25% of the US population in 2001 (up from 0.2% in 1984) makes antibodies against PEG thus potentially sensitizing patients to PEG-drugs. The process of adding natural "self" heparosan polymers to therapeutic cargo (Caisson Biotech's HEPylation platform) has several advantages over PEG-based processes including higher biocompatibility, better synthesis control, and lower potential for immunogenicity which should translate into reduced side effects with less frequent drug injections;our letters of support from pharma state their desires for such a PEG substitute. In this Phase I SBIR, our goal is the synthesis and initial testing in animal efficacy and toxicology model systems of a superior replacement for the PEG- drug, Neulasta ($4.6 Billion sales in 2009), which is commonly employed to prevent infection due to low white blood cell levels after anti-cancer chemotherapy.